Previous drug eluting devices, such as, for example, vascular stents have generally failed to restrain hydrophilic medicines at the site of injury or damaged tissue. Although the use of the present invention is not limited to deployment at the sites of vascular injury, the problems encountered in that model serve to frame this invention and how it provides a new approach to previously encountered roadblocks in the local treatment of injury or disease.
Drug eluting stent (DES) technology has been known in the art for approximately ten years. Ten years ago, a major problem faced by angiographers was that once a stent was deployed in a vessel, especially in an end-vessel system such as the coronary system, there was a high incidence of vascular thrombosis in the newly deployed stent lumen. At the time, investigators focused their efforts on preventing acute thrombosis by delivering Heparin, a potent hydrophilic parenteral anticoagulant, from the stent surface (U.S. Pat. No. 5,383,928). Restenosis, the process of late lumen loss due to neointimal hypertrophy, was also investigated by the elution of both hydrophobic and hydrophilic molecules to attempt to slow or prevent this process (U.S. Pat. No. 5,464,650), but these, too, efforts were largely unsuccessful. The problem was either that the treatment compounds were not sufficiently restrained by the stent or were rapidly solubilized in the aqueous environment of blood and quickly washed away from the site of injury.
Recently, Tedeschi et al (U.S. Pat. No. 6,645,518) refer to the use of a specialized coating which is capable of binding and releasing hydrophobic medicines in solution. They also refer to incorporation of hydrophilic medicines in a polymeric compound composed of a polyisocyanate; an amine donor and/or a hydroxyl donor; an isocyanatosilane adduct having terminal isocyanate groups and at least one hydrolysable alkoxy group bonded to silicon; together with a polymer base. This mixture swells when hydrated and can as such be loaded with medicine dispersed in the hydrating solution. After deployment in aqueous solution, the medicine is then released. However, they describe no means to restrain the medicine after release such that it remains available to damaged tissues locally. Once released, the hydrophilic medicine is free to drift away in solution from the treatment site away from where it is needed.
Also described in the work of Tedeschi et al. (U.S. Pat. No. 6,645,518) is how covalent bonds can be used to regulate drug release: “In a most preferred embodiment, the nucleophilic nitrogen atoms of the polyurea network are allowed to react with an organic or inorganic compound to form a covalent bond. The resulting coating-active agent bond preferably cleaves to release the active agent when used on a medical device in an environment which can cleave the bond.” Once released, however, the treating material is free to float away.
Several other investigators have discussed the covalent linking of a macromolecule to the surface of a device to alter the local treating environment. For example, Ward and others (U.S. Pat. Nos. 4,861,830, 5,589,563) refer to methods of treating the surface of a device to improve flow dynamics of blood along the surface of a device by changing the hydrophobicity of polymers attached to the surface. These properties have also been referred to by McGee and colleagues (U.S. Pat. No. 6,599,559). Schwartz, et al. (U.S. Pat. No. 5,607,463) refers to how adding atoms of group 5b of the periodic table can be used to improve the binding properties of a polymer to a metal device surface. In contrast, Saffran has disclosed the use of elutable molecules and molecules bound by a hydrolysable bond to alter the biology of neighboring cells in vivo through a method of “directional presentation” of a treating material (U.S. Pat. Nos. 5,660,225, 5,466,262 and 5,653,760).
Clapper (U.S. Pat. No. 5,744,515) refers to the promotion of graft endothelialization by directional presentation of cell adhesion molecules on the device surface. The affixed molecules in Clapper are said to have an adhesive function. Horvath et al. (U.S. Pat. No. 6,663,863) refer to the use of medicines derived from the complement cluster domains of the immune system to inhibit cell adhesion. Injection of such compounds at the time of stenting is said to inhibit recruitment and/or adhesion of cells to the stent. No means for limiting the systemic response of these drugs to only those cells in the vicinity of the stent is disclosed.
What is needed, however, is a means to both deliver and restrain medicinal functional groups primarily at the site of injury without their floating away in the blood stream and without their being “used up” after contact with the first cell to utilize them.
One embodiment of the present invention provides apparatus and methods of tissue stabilization and/or treatment by which the functional elements of treating materials are retained at the site of injury.
Another embodiment of the present invention provides methods and apparatus that serve as a surface for catalysis of cell membrane reactions, thereby providing a substantially undepletable source of treating material to tissues adjacent to the device.
Another embodiment of the present invention provides methods and apparatus for treatment of fluids within the body by providing on the surface of the device the active sites of specific plasma-borne enzymes, hormones or growth factors, thereby permitting device-directed catalysis of specific humeral reactions.
A further embodiment of the present invention provides methods and apparatus for surface catalysis, the chemical properties of which can be modified after the device has been deployed.
A further embodiment of this invention provides methods and apparatus for surface catalysis that can present a multitude of differing molecular moieties simultaneously.
A further embodiment of the present invention provides reactive surfaces and methods capable of converting pro-drugs to biologically active drugs at the site of device deployment.
Additional embodiments of the present invention provide methods and devices for surface catalysis that can be deployed via endoscope, catheter, needle, or open surgical procedure that can provide structural support to hollow viscera, solid organs, or blood vessels.
Other embodiments and advantages of the invention will be apparent from the following summary and detailed description together with the accompanying Figures.